1-aryloxy-4-amino-2-butanols

ABSTRACT

Novel 1-aryloxy-4-amino-2-butanols of the formula 
     
         ArO--CH.sub.2 --CHOH--CH.sub.2 --CH.sub.2 --NR.sup.1 R.sup.2 
    
     wherein Ar is 1-naphthyl, 2-naphthyl, indene-4(or 5-)yl, 3-(or 5-)chloro-2-pyridyl, phenyl, monosubstituted phenyl or di-substituted phenyl, R 1  is lower alkyl, phenyl, phenylalkyl, 2-hydroxymethyl-2-propyl, adamantyl or lower-cycloalkyl, R 2  is hydrogen or lower alkyl, wherein R 1  and R 2  together with the adjacent nitrogen from a heterocyclic residue and the pharmaceutically acceptable acid addition salts thereof having local anesthetic, beta-adrenergic blocking, antihypertensive and antiarrhythmic properties are disclosed. The compounds are prepared by reacting novel 1-aryloxy-4-chloro-2-butanols with amines. Methods for the preparation of the novel 1-aryloxy-4-chloro-2-butanol intermediates are also disclosed.

REFERENCE TO PARENT APPLICATIONS

This is a continuation of application Ser. No. 904,113 filed Sept. 4, 1986.

The present application which is a continuation-in-part of copending application Ser. No. 06/683,765 filed on Dec. 19, 1984, which application is a divisional of application Ser. No. 06/418,939 filed on Sept. 16, 1982, now abandoned, which is a divisional of application Ser. No. 05/813,056 filed on July 5, 1977, now U.S. Pat. No. 4,379,167 issued Apr. 5, 1983, which application is a continuation-in-part of application Ser. No. 05/730,498 filed Oct. 17, 1976, now abandoned, which is a continuation of application Ser. No. 05/618,984 filed Oct. 2, 1975, now abandoned, which is a continuation-in-part application of application Ser. No. 05/518,122 filed Oct. 25, 1974, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to certain organic compounds which may be referred to as disubstituted-2-butanols and is more particularly concerned with 1-aryloxy-4-amino-2-butanols and with processes for the production thereof, intermediate products useful in the preparation thereof and with processes for the preparation of such intermediates, compositions containing the 1-aryloxy-4-amino-2-butanols as active ingredients and methods for the use thereof.

2. Discussion of the Prior Art

The compounds which are the subject of this invention are related to known 1-aryloxy-3-amino-2-propanols as having beta-adrenergic blocking, anticonvulsant, sedative and tranquilizing activity. Among the United States patents disclosing the aforementioned 1,3-disubstituted-2-propanols and their pharmacological properties are U.S. Pat. Nos. 3,337,628; 3,415,873; 3,432,545; and 3,520,919. U.S. Pat. No. 3,337,628 in particular discloses 1-isopropyl-amino-3-(1-naphthyloxy)-2-propanol which compound is a potent betablocking agent.

SUMMARY OF THE INVENTION

The present invention is especially concerned with novel 1-aryloxy-4-amino-2-butanols having the formula:

    ArO--CH.sub.2 --CHOH--CH.sub.2 --CH.sub.2 --NR.sup.1 R.sup.2 Formula I

wherein;

Ar is 1-naphthyl, 2-naphthyl, indene-4(or 5-)yl, 3-(or 5-)chloro-2-pyridyl, phenyl, monosubstituted phenyl or disubstituted phenyl,

R¹ is lower alkyl, phenyl, phenylalkyl, 2-hydroxymethyl-2-propyl, adamantyl or lower cycloalkyl,

R² is hydrogen or lower alkyl,

R¹ and R² together with the adjacent nitrogen form a heterocyclic residue, and

pharmaceutically acceptable acid addition salts thereof.

The compounds of the invention having the foregoing Formula I are generally characterized by important and significant pharmacological activity, which is indicative of their use in counteracting certain phsyiological abnormalities in an animal body. The compounds possess local anesthetic, beta-adrenergic blocking, anti-hypertensive and antiarrhythmic properties.

The 1-aryloxy-4-amino-2-butanols were evaluated for pharmacological activity and were found to possess antiarrhythmic properties against experimentally induced cardiac arrhythmias in dogs. The prior art homolog 1,3-disubstituted-2-propanols also have antiarrhythmic activity. However, in contrast to the prior art 2-propanols, the novel 2-butanols of the present invention have minimal beta-adrenergic blocking activity, enabling them to be employed in controlling moderate to serious arrhythmias without the dangers of cardiac failure and respiratory difficulties, which dangers are attendant when the prior art 1,3-disubstituted-2-propanols having potent beta-adrenergic blocking activity are used in controlling cardiac arrhythmias.

Compounds of Formula I wherein Ar is 1-naphthyl and --NR¹ R² is lower-alkylamino, lower cycloalkylamino wherein lower cycloalkyl has from 5 to 7 carbon atoms, phenylalkylamino, 2-hydroxymethyl-2-propylamino or phenylamino represent preferred compounds for their antiarrhythmic activity.

Compounds of Formula I wherein Ar is an ortho-lower-alkoxyphenoxy radical, particularly methoxy- and ethoxy-phenoxy radicals, and --NR¹ R² is lower-alkylamino, lower cycloalkylamino wherein lower cycloalkyl has from 5 to 7 carbon atoms, phenylalkylamino, 2-hydroxymethyl-2-propylamino or phenylamino are also of particular interest for their antiarrhythmic activity.

To illustrate the utility of the compounds of this invention the following tabulation indicates the amount of certain representative compounds of this invention to correct ouabain-induced arrhythmias in anesthetized dogs.

                  TABLE 1                                                          ______________________________________                                                      Average Corrective                                                                           No. of                                              Example      Dose (mg/kg, i.v.)                                                                           Tests                                               ______________________________________                                         46           12.5          1                                                   47           7.0           2                                                   1            2.75          2                                                   14           19.0          2                                                   15           3.5           2                                                   17           5.0           2                                                   7            1.75          2                                                   19           9.3           2                                                   6            5.5           1                                                   23           9.3           2                                                   3            3.5           2                                                   28           3.0           2                                                   30           2.0           2                                                   37           8.0           1                                                   42           2.25          2                                                   73           3.25          2                                                   74           2.5           1                                                   75           4.0           2                                                   ______________________________________                                    

It is accordingly an object of this invention to provide novel 1-aryloxy-4-amino-2-butanols which are useful pharmacologically because of their aforesaid types of activity, processes for the production thereof, and intermediate products useful in the preparation thereof and processes for the production of such intermediates which in themselves have useful pharmacological activity. A further object is to provide novel compositions containing 1-aryloxy-4-amino-2-butanols as active ingredients and methods for their use. Other objects of the invention will be apparent to one skilled in the art, and still other objects will become apparent hereinafter.

In the definitions of the symbols in foregoing Formula I and where they appear elsewhere throughout this specification, the terms have the following significance.

The term "lower alkyl" as used herein includes straight and branched chain radicals of up to eight carbon atoms inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like.

The term "lower alkoxy" has the formula --O--lower alkyl.

When halogen is referred to herein, preferably but not necessarily, a halogen of atomic weight in excess of eighteen but not greater than eighty is employed.

The term "heterocyclic residue" as used herein includes basic saturated monocyclic heterocyclic radicals and basic unsaturated monocyclic heterocyclic radicals of less than twelve carbon atoms, as exemplified by piperidino; (lower alkyl)piperidino, e.g., 2-, 3-, or 4-(lower alkyl)piperidino; pyrrolidino; morpholino; di-(lower alkyl)morpholino, e.g., 3,5-dimethylmorpholino; 2,6-dimethylmorpholino; piperazino; (lower alkyl)piperazino (e.g., N⁴ -methylpiperazino); phenylpiperazino (e.g., N⁴ -phenylpiperazino); 1,2,3,4-tetrahydroisoquinolyl; 1,2,3,6-tetrahydropyridino, 4-(2-pyridyl)piperazino, and phthalimido.

Included in the term "phenylalkyl" are groups such as benzyl, phenethyl, methylbenzyl, phenpropyl, and the like.

The term "lower cycloalkyl" includes cyclic radicals having up to eight carbon atoms and includes radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "phenyl" includes the unsubstituted phenyl radical, the substituted phenyl radical and the disubstituted phenyl radical. Among the suitable substituted and disubstituted phenyl radicals are those which are substituted by any radical or radicals which are not reactive or otherwise interfering under the conditions of reaction in preparing the desired compound, such radicals including lower alkyl, lower alkoxy, trifluoromethyl, acetyl, acetylamino, halo, trifluoromethyl, and phenyl. The substituted phenyl radicals have preferably one or two substituents such as those given above and, furthermore, the substituents can be in various available positions of the phenyl nucleus and, when more than one substituent is present, can be the same or different and can be in various combinations relative to each other. The lower alkyl and lower alkoxy substituents each have preferably from one to four carbon atoms which can be arranged as straight or branched chains. A total of nine carbon atoms in all ring substituents, making a total of fifteen carbon atoms in the radical, is the preferred maximum.

The compounds of the invention are most conveniently employed in the form of phrmaceutically acceptable acid addition salts. Such salts have improved water solubility over the free bases. Appropriate acid addition salts are those derived from mineral acids such as hydrochloric, hydrobromic, sulfuric and phosphoric; and organic acids such as acetic, citric, lactic, maleic, oxalic, fumaric and tartaric. The preferred acid addition salt is the hydrochloride. The acid addition salts are conveniently prepared by reaction of the basic compounds with the selected acid, either or both of which may be in the form of ether, alcohol or acetone solutions.

The present invention also includes the novel 1-aryloxy-4-chloro-2-butanols of Formula IV which are useful as intermediates for preparing the final amine products of Formula I and they may be prepared by the process diagrammed in Chart I, wherein all of the symbols have the meanings given previously. ##STR1##

The 1-aryloxy-4-chloro-2-butanols (IV) are generally prepared by treating an aqueous basic solution or an aqueous-alcoholic basic solution of a phenol, a substituted phenol or an aryl compound having an acidic hydroxyl group of Formula II with 1,4-dichloro-2-butanol III. The addition is carried out at or below 70° C., preferably at from about 30° C. to about 65° C. over a period of from about three hours to about eight hours. Subsequent to the addition the reaction mixture is heated at from about 50° C. to about 75° C., preferably at 60° C. to 70° C. for a period of from about six hours to about forty-eight hours, usually for a period of from twelve hours to eighteen hours. The 1-aryloxy-4-chloro-2-butanol is isolated from the reaction mixture by extraction using a suitable organic solvent as, for example, ether, isopropyl ether or chloroform, evaporation of the solvent after drying to give the 2-butanol which is isolated by suitable means such as distillation or crystallization. Alternatively, the 1-aryloxy-4-chloro-2-butanol can be prepared by adding an aqueous basic solution to a mixture of the phenol or the compound having an acidic hydroxyl group and 1,4-dichloro-2-butanol at a rate so as to maintain the reaction mixture at a pH of from about 9.0 to about 10.5, preferably at a pH of 9.5 to 10.0. The product is isolated as described hereinabove.

The following preparations are given by way of illustration only and are in no event to be construed as limiting.

PREPARATION 1 4-Chloro-1-phenoxy-2-butanol

To a mixture which contained 282 g. (3 moles) of phenol, one liter of water and 300 ml. of 50% sodium hydroxide was added slowly with stirring at 60° C. 443.36 g. (3.1 moles) of 1,4-dichlorobutanol. Stirring was continued at 60° C. for 16 hr. The resulting mixture was extracted twice with one liter of ether and the combined ether extracts were washed with water to neutrality and dried overnight over sodium sulfate. The dried ether mixture was concentrated to dryness under reduced pressure. The residue was distilled and yielded 435 g. of product which was collected at 135°-138° C./0.05 mm. The product solidified and was recrystallized using pet. ether (60°-110° C.) to give a white crystalline solid which melted at 52°-54° C.

Analysis: Calculated for C₁₀ H₁₃ ClO₂ : C, 59.86; H, 6.53. Found: C, 59.72; H, 6.37.

PREPARATION 2 4-Chloro-1-(2-chlorophenoxy)-2-butanol

To a mixture of 129 g. (1 mole) of 2-chlorophenol, 60 g. of potassium hydroxide, 100 ml. of water and 400 ml. of isopropanol was added 1.3 moles (185.9 g.) of 1,4-dichloro-2-butanol with stirring at 50° C. The resulting mixture was heated in a steam bath at 65° C. overnight and extracted with 300 ml. of isopropyl ether. The ether extract was washed successively with 1N sodium hydroxide, water and dried over sodium sulfate. The dried ether solution was concentrated and the oily residue was distilled under reduced pressure yielding 152 g. of an oily substance (b.p. 130°-131° C./0.01 mm.).

Analysis: Calculated for C₁₀ H₁₅ ClO₂ : C, 51.08; H, 5.15. Found: C, 51.13; H, 5.14.

PREPARATION 3 4-Chloro-1-(3,5-dimethylphenoxy)-2-butanol

To a mixture of 245 g. (2 moles) of 3,5-dimethylphenol and 2 liters of 2N sodium hydroxide was added 2.5 moles of 1,4-dichlorobutanol with stirring at 65° C. overnight. The solid precipitate which separated on cooling was filtered and washed with water to neutrality. Recrystallization with isopropyl ether yielded 375 g. of white crystalline solid which melted at 74°-76° C.

Analysis: Calculated for C₁₂ H₁₇ ClO₂ : C, 62.02; H, 7.49. Found: C, 63.96; H, 7.66.

PREPARATION 4 4-Chloro-1-(4-chloro-3-methylphenoxy)-2-butanol

To a mixture of 286 g. (2 moles) of 3-methyl-4-chlorophenol, 700 ml. of tertiary butanol, 700 ml. of water and 3.0 moles of 1,4-dichloro-2-butanol, sodium hydroxide (2.9 moles, 230 g. in 700 ml. water) was added with stirring at 40° C. to maintain a pH of 9.5-10.0 as the reaction progressed. The addition was 10 hr.; the reaction was stirred at 40° C. for 48 hr. The resulting reaction mixture was extracted with chloroform sodium hydroxide at 25° C. The chloroform extract was washed with sodium sulfate. The dried chloroform solution was concentrated and the residue was distilled under reduced pressure to give 110.9 g. of the product which distilled at 135°-143° C./0.007 mm. and melted at 87°-89° C. after recrystallization with isopropanol and pet. ether (30.60°).

Analysis: Calculated for C₁₁ H₁₄ Cl₂ O₂ : C, 53.03; H, 5.66. Found: C, 53.11; H, 5.61.

PREPARATION 5 4-Chloro-1-(4-chloro-2-methylphenoxy)-2-butanol

4-Chloro-1-(4-chloro-2-methylphenoxy)-2-butanol was prepared according to the procedure of Preparation 4 using 105 g. (0.74 mole) of 2-methyl-4-chlorophenol, 171.5 g. (1.2 mole) of 1,4-dichloro-2-butanol, 50.3 g. of sodium hydroxide, 300 ml. of water and 300 ml. of tertiary butanol. There was obtained 84 g. (45.5%) of product which distilled at 135° C./0.01 mm.

Analysis: Calculated for C₁₁ H₁₄ O₂ Cl₂ : C, 53.03; H, 5.66. Found: C, 53.41; H, 5.70.

PREPARATION 6 4-Chloro-1-(1-naphthyloxy)-2-butanol

To a mixture of 1 mole (147 g.) of 1-naphthol, 350 ml. of water and 2 moles (112 g.) of potassium hydroxide was added at 54° C. 1 mole (143 g.) of 1,4-dichloro-2-butanol. The temperature of the reaction mixture was kept below 60° C. during the addition of the chlorobutanol. The reaction mixture was heated at 65° C. for 12 hr., then mixed with 500 ml. of water and 350 ml. of chloroform. The chloroform layer was separated, washed with water, dried over sodium sulfate, concentrated and the residual oil distilled under reduced pressure to give 128 g. of a crystalline solid which was distilled at 162°-165° C./0.01 mm. The solid was recrystallized with ether and pet. ether (30°-60°) to give material melting at 75°-77° C.

Analysis: Calculated for C₁₄ H₁₅ O₂ Cl: C, 67.07; H, 6.03. Found: C, 67.19; H, 6.19.

PREPARATION 7 4-Chloro-(4-biphenylyloxy)-2-butanol

To a solution of 1 mole (158 g.) of 4-phenylphenol 100 g. of sodium hydroxide and 500 ml. of water was added 1 mole (143.02 g.) of 1,4-dichloro-2-butanol with stirring at 40° C. The resulting mixture was heated at 68° C. in a steam bath for 6 hr., cooled and extracted with 300 ml. of chloroform. The chloroform extract was washed with water to neutrality, dried over sodium sulfate and concentrated to dryness. The solid residue was recrystallized with isopropanol and yielded 180 g. of a white crystalline solid which melted at 123°-124° C.

Analysis: Calculated for C₁₆ H₁₇ ClO₂ : C, 69.44; H, 6.19. Found: C, 69.79; H, 6.22.

PREPARATION 8 4-Chloro-1-(3-trifluoromethylphenoxy)-2-butanol

To a mixture of 0.5 mole (75 g.) of m-trifluoromethylphenol, 1 mole (56 g.) of potassium hydroxide, 100 ml. of water and 400 ml. of isopropanol was added 0.6 mole (84 g.) of 1,4-dichloro-2-butanol with stirring at temperature below 55° C. The resulting reaction mixture was heated at 65° C. for 20 hr., mixed with 2 liters of water, and extracted with 400 ml. of isopropyl ether. The ether extract was washed with 0.5N sodium hydroxide and then with water, dried over sodium sulfate and distilled under reduced pressure. The distillate which was collected at 120°-124° C./0.01 mm. solidified at room temperature and melted at 50°-52° C.

Analysis: Calculated for C₁₁ H₁₂ ClF₃ O₂ : C, 49.18; H, 4.50. Found: C, 49.35; H, 4.47.

PREPARATION 9 4-Chloro-1-(4-chlorophenoxy)-2-butanol

4-Chloro-1-(4-chlorophenoxy)-2-butanol was prepared using the procedure of Preparation 7 from 45 g. (0.5 mole) of p-chlorophenol, 72 g. (0.5 mole) of 1,4-dichloro-2-butanol, 40 g. (1.0 mole) of sodium hydroxide and 400 ml. of water to give 85 g. (36.1%) of product which melted at 62°-64° C. after recrystallization from isopropanol.

Analysis: Calculated for C₁₀ H₁₅ ClO₂ : C, 51.09; H, 5.14. Found: C, 51.76; H, 5.12.

PREPARATION 10 4-chloro-1-(2-methoxyphenoxy)-2-butanol

To a mixture of 2 moles (248.26 g.) of 2-methoxyphenol, 4 moles (160 g.) of sodium hydroxide, 250 ml. of water and 1 liter of isopropanol was added with stirring 2.2 moles (314.64 g.) of 1,4-dichloro-2-butanol. The mixture was refluxed gently overnight. The reaction mixture was extracted with 1 liter of isopropyl ether, dried over sodium sulfate and distilled under reduced pressure. The distillate which was collected at 136°-138° C./0.015 mm. (396.8 g.) solidified to a white crystalline solid which melted at 48°-50° C.

Analysis: Calculated for C₁₁ H₁₄ O₃ Cl: C, 57.52; H, 6.14. Found: C, 57.49; E, 6.54.

Using the procedures disclosed in Preparations 1-10, starting from the appropriate phenol II and 1,4-dichloro-2-butanol III, various other 1-aryloxy-4-chloro-2-butanols IV are prepared.

PREPARATION 11

4-Chloro-1-(2-methyl-5-chlorophenoxy)-2-butanol, b.p. 135°-8° C./0.05 mm. was prepared from 2-methyl-5-chlorophenol and 1,4-dichloro-2-butanol.

PREPARATION 12

4-Chloro-1-(2-naphthyloxy)-2-butanol, m.p. 101°-102° C., was prepared from 2-naphthol and 1,4-dichloro-2-butanol.

PREPARATION 13

4-Chloro-1-(4-acetylaminophenoxy)-2-butanol, m.p. 125°-128° C., was prepared from 4-acetylaminophenol and 1,4-dichloro-2-butanol.

PREPARATION 14

4-Chloro-1-(3-chloro-2-pyridyloxy)-2-butanol, m.p. 56°-58° C., was prepared from 3-chloro-2-hydroxypyridine and 1,4-dichloro-2-butanol.

PREPARATION 15

4-Chloro-1-(5-chloro-2-pyridyloxy)-2-butanol, was prepared from 5-chloro-2-hydroxypyridine and 1,4-dichloro-2-butanol.

PREPARATION 16

4-Chloro-1-(inden-5-yloxy)-2-butanol, m.p. 56°-58° C., was prepared from 6-hydroxyindene and 1,4-dichloro-2-butanol.

PREPARATION 17

4-Chloro-1-(3-chlorophenoxy)-2-butanol, 60°-62° C., was prepared from 3-chlorophenol and 1,4-dichloro-2-butanol.

PREPARATION 18

4-Chloro-1-(2-ethoxyphenoxy)-2-butanol, b.p. 130°-132° C./0.01 mm. was prepared from 2-ethoxyphenol and 1,4-dichloro-2-butanol.

PREPARATION 19

4-Chloro-1-(4-acetylphenoxy)-2-butanol, m.p. 82°-85° C., was prepared from 4-acetylphenol and 1,4-dichloro-2-butanol.

PREPARATION 20

4-Chloro-1-(o-phenylphenoxy)-2-butanol, b.p. 156°-160° C./0.25 mm., was prepared from o-phenylphenol and 1,4-dichloro-2-butanol.

PREPARATION 21 1-(4-Bromophenoxy)-4-chloro-2-butanol

To a rapidly stirring solution of 22.5 g (0.56 mole) of sodium hydroxide in 400 ml of water was added, dropwise, 73.8 g (0.52 mole) of freshly distilled 1,4-dichloro-2-butanol. The mixture was stirred for 15 min at ambient temperature. To this mixture was added, over a 45 min period, a solution obtained by adding 75.0 g (0.43 mole) of 4-bromophenol to a solution of 18.0 g (0.47 mole) of sodium hydroxide in 430 ml of water. The mixture was stirred vigorously for 30 hr and then cooled to an ice bath. The suspended solid was collected by filtration, rinsed with water several times and air dried. Recrystallization from ethyl ether-petroleum ether (b.p. range 30°-60° C.) gave 44.2 g (37%) of white solid, m.p. 75°-78° C.

Analysis: Calculated for C₁₀ H₁₂ BrClO₂ : C, 42.96; H, 4.33. Found: C, 43.16; H, 4.34.

PREPARATION 22 4-chloro-1-(4-fluorophenoxy)-2-butanol

Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-fluorophenol to give white title compound, m.p. 53°-55° C. in 30% yield.

Analysis: Calculated for C₁₀ H₁₂ ClFO₂ : C, 54.93; H, 5.53. Found: C, 55.20; H, 5.56.

PREPARATION 23 4-Chloro-1-(4-methylphenoxy)-2-butanol

Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-methylphenol to give white title compound, m.p. 62°-64° C. in 42% yield.

Analysis: Calculated for C₁₁ H₁₅ ClO₂ : C, 61.54; H, 7.04. Found: C, 61.62; H, 7.17.

PREPARATION 24 4-Chloro-1-(4-methoxyphenoxy)-2-butanol

Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-methoxyphenol to give white title compound, m.p. 65°-68° C. in 42% yield. The recrystallizing solvent was diethyl ether.

Analysis: Calculated for C₁₁ H₁₅ ClO₃ : C, 57.27; H, 6.55. Found: C, 57.39; H, 6.62.

PREPARATION 25 4-Chloro-1-(4-nitrophenoxy)-2-butanol

Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-nitrophenol to give white title compound, m.p. 60°-63° C.

Analysis: Calculated for C₁₀ H₁₂ ClNO₄ : C, 48.89; H, 4.92; N, 5.71. Found: C, 48.92; H, 4.94; N, 5.86.

PREPARATION 26 4-Chloro-1-(3,4-dichlorophenoxy)-2-butanol

Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 1,4-dichloro-2-butanol to give white title compound, m.p. 82°-84° C. in 35% yield.

Analysis: Calculated for C₁₀ H₁₁ Cl₃ O₂ : C, 44.56; H, 4.11. Found: C, 44.76; H, 4.17.

PREPARATION 27 4-(4-Chloro-2-hydroxybutoxy)benzonitrile

Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-cyanophenol to give white title compound, m.p. 78°-80° C. in 13% yield.

Analysis: Calculated for C₁₁ H₁₂ ClNO₂ : C, 58.55; H, 5.36; N, 6.21. Found: C, 58.61; H, 5.41; N, 6.23.

PREPARATION 28 4-Chloro-1-[4-(1,1-dimethylethyl)phenoxy]-2-butanol

Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-t-butylphenol to give white title compound, m.p. 45°-47° C. Petroleum ether (30°-60° C.) was the recrystallizing solvent.

Analysis: Calculated for C₁₄ H₂₁ ClO₂ : C, 65.49; H, 8.24. Found: C, 65.57; H, 8.31.

PREPARATION 29 4-(4-Chloro-2-hydroxybutoxy)benzamide

Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-hydroxybenzamide to give white title compound, m.p. 150°-153° C. in 25% yield. The recrystallizing solvent was 95% ethanol.

Analysis: Calculated for C₁₁ H₁₄ ClNO₃ : C, 54.22; H, 5.79; N, 5.75. Found: C, 54.24; H, 5.78; N, 5.71.

PREPARATION 30 1-[4-(4-Chloro-2-hydroxybutoxy)phenyl]ethanone

Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-hydroxyacetophenone to give cream colored solid, m.p. 75°-77° C. Recrystallizing solvent was a mixture of ethanol-diethyl ether.

Analysis: Calculated for C₁₂ H₁₅ CiO₃ : C, 59.39; H, 6.23. Found: C, 59.57; H, 6.34.

PREPARATION 31 N-[4-(4-Chloro-2-hydroxybutoxy)phenyl]acetamide

To a solution of 500 g (3.5 mole) of 1,4-dichloro-2-butanol was added, dropwise, 500 ml (6.25 mole) of a 50% sodium hydroxide solution. The mixture was stirred for 16 hr and then 500 ml of water was added, dropwise, with the temperature maintained below 35° C. The mixture was extracted with 500 ml of isopropyl ether, dried over sodium sulfate and concentrated to give an oil which was purified by distillation. To 14.3 g (0.1 mole) of the purified epoxide was added a solution of 15.1 g (0.1 mole) of 4-acetamidophenol in 150 ml of 2-propanol and 4 g of (0.1 mole) of sodium hydroxide in 10.0 ml of water. The mixture was stirred for 15 hr and then poured into 400 ml of water at 0° C. The crude, collected solid was washed with water and allowed to air dry. The solid was suspended in 350 ml of acetone, collected by filtration, and washed with additional portions of acetone. The filtrate was concentrated under reduced pressure to give 13.8 g (53% yield) of solid. A portion of this solid was recrystallized from tetrahydrofuran to give cream-colored solid, m.p. 124°-127° C.

Analysis: Calculated for C₁₂ H₁₆ ClNO₃ : C, 55.93; H, 6.26; N, 5.44. Found: C, 56.19; H, 6.38; N, 5.44.

The preparation of the novel 1-aryloxy-4-amino-2-butanols I of the present invention is designated in the following reaction sequence: ##STR2## wherein all of the symbols have the meanings given hereinabove.

In the reaction sequence the 1-aryloxy-4-chloro-2-butanol (IV) is reacted with an amine (V) to give the novel 1-aryloxy-4-amino-2-butanols (I). The foregoing reaction can be carried out by (A) heating a mixture of the chloro compound and the amine with a solvent in a steel bomb, (B) heating a mixture of the chloro compound and the amine without a solvent in a steel bomb, (C) refluxing a mixture of the chloro compound, the amine and a solvent at atmospheric pressure or (D) heating a mixture of the chloro compound and the amine without a solvent at atmospheric pressure and at a suitable temperature. The selected procedure is somewhat dependent on the nature of the amine reactant. Thus, when the amine is a low molecular volatile amine process A or B is preferred and the bomb contents are heated at from about 100° C. to about 150° C. for a period of from about 12 hours to about 24 hours. When the amine is a high molecular weight non-volatile amine or an amine having low volatility, process C or D is preferred and the reaction mixture is refluxed at the temperature of the solvent used or the mixture is heated at from about 100° C. to about 150° C. The reaction time can be varied, reaction times being somewhat shorter when the chloro compound and the amine are reacted together in the absence of a solvent and a higher reaction temperature is employed. The reaction product in each case is isolated by conventional acid-base extraction procedures and the free base, if desired, is converted to a pharmaceutically acceptable acid addition salt which is further purified by crystallization from a suitable solvent or solvent system. 1-Aryloxy-4-amino-2-butanols which do not form well defined salts can be purified by vacuum distillation.

Examples 1-6 illustrate the preparation of the novel 1-aryloxy-4-amino-2-butanol compounds of the present invention by one of the four optional processes. Table II summarizes the physical data of another group of additional compounds within the scope of Formula I and indicates the process used to prepare each compound.

The preparation of still another group of compounds within the scope of Formula I is described in Examples 78 to 122.

Table III contains the analytical data of the compounds listed in Table II.

EXAMPLE 1 4-Isopropylamino-1-(1-naphthyloxy)-2-butanol Hydrochloride

A mixture of 27.1 g. (0.1 mole) of 1-(1-naphthyloxy)-2-hydroxybutyl chloride and 100 ml. of isopropylamine in a steel bomb was heated at 120° C. for 24 hours. The reaction mixture was mixed with 300 ml. of 6N hydrochloric acid and extracted with ether at room temperature. The acidic aqueous solution was made basic, extracted with isopropyl ether, dried over sodium sulfate, then concentrated to dryness. The residue was dissolved in isopropanol and mixed with ethereal hydrogen chloride. The white crystalline precipitate was recrystallized from isopropanol and isopropyl ether to give hydrochloride salt which melted at 126°-128° C.

Analysis: Calculated for C₁₇ H₂₄ ClNO₂ : C, 65.90; H, 7.81; N, 4.52. Found: C, 65.67; H, 7.91; H, 4.34.

EXAMPLE 2 4-(1,2,3,4-Tetrahydroisoquinolin-2-yl)-1-(1-naphthyloxy)-2-butanol Hydrochloride

A mixture of 12.5 g. (0.05 mole) of 1-(1-naphthyloxy)-2-hydroxybutyl chloride, 9.97 g. (0.075 mole) of 1,2,3,4-tetrahydroisoquinoline and 300 ml. of isopropanol was refluxed for 15 hr. On standing at room temperature a crystalline precipitate formed. The mixture was filtered and the filtrate concentrated to dryness under reduced pressure. The semi-solid residue which crystallized was recrystallized from acetone. The 12.2 g. of crystalline solid material melted at 169°-171° C.

Analysis: Calculated for C₂₃ H₂₆ ClNO₂ : C, 71.96; H, 6.83; N, 3.65. Found: C, 71.69; H, 6.76; N, 3.60.

EXAMPLE 3 1-(1-Naphthyloxy)-4-phenethylamino-2-butanol Hydrochloride

A mixture of 12.5 g. (0.05 mole) of 1-(1-naphthyloxy)-2-hydroxybutyl chloride and 14.5 g. (0.1 mole) of phenethylamine was heated at 120° C. for 20 min. on a hot plate. The resulting mixture was mixed with 250 ml. of acetone, heated to boiling and then filtered at room temperature. The filtrate was treated with 50 ml. of ethereal hydrogen chloride. The resulting white precipitate was filtered. The white crystalline solid was recrystallized from acetone and yielded 11.8 g. of the hydrochloride salt which melted at 163°-165° C.

Analysis: Calculated for C₂₂ H₂₅ NO₂ Cl: C, 71.05; H, 7.05; N, 3.77. Found: C, 70.99; H, 6.98; N, 3.61.

EXAMPLE 4 1-(2-Chlorophenoxy)-4-(1,2,3,4-tetrahydroisoquinolyl)-2-butanol Hydrochloride Hydrate

A mixture of 11.8 g. (0.05 mole) of 1-(2-chlorophenoxy)-2-hydroxybutyl chloride, 13.3 g. (0.1 mole) of 1,2,3,4-tetrahydroisoquinoline and 100 ml. of n-butanol was heated in a steel bomb at 120° C. for 24 hr. The reaction mixture was filtered at room temperature, the filtrate was mixed with 200 ml. 3N hydrochloric acid and extracted twice with 100 ml. isopropyl ether. The aqueous acidic solution was made basic and extracted with isopropyl ether and treated with ethereal hydrogen chloride. Recrystallization with isopropanol yielded 6 g. of the hydrochloride hydrate of the product which melted at 118°-120° C.

Analysis: Calculated for C₁₉ H₂₅ Cl₂ NO₃ : C, 59.07; H, 6.52; H, 3.63. Found: C, 59.08; H, 6.51; N, 3.55.

EXAMPLE 5 4-(Isopropylamino)-1-(o-methoxyphenoxy)-2-butanol Hydrochloride

A mixture which contained 11.6 g. (0.05 mole) of 1-(2-methoxyphenoxy)-2-hydroxybutyl chloride, 50 ml. of isopropyl amine and 100 ml. of n-butanol was charged in a steel bomb and heated at 120° C. for 24 hr. The resulting reaction mixture was filtered. The filtrate was concentrated to dryness and mixed with 200 ml. of 3N hydrochloric acid, extracted with ether and the aqueous layer was made basic. The base insoluble oil was extracted into isopropyl ether, dried over sodium sulfate and concentrated to dryness. The residue was dissolved in isopropanol and mixed with 20 ml. ethereal hydrogen chloride. The gummy precipitate recrystallized using isopropyl ether and isopropanol. The hydrochloride (8.3 g.) melted at 83°-85° C.

Analysis: Calculated for C₁₄ H₂₄ ClNO₃ : C, 58.02; H, 8.35; H, 4.83. Found: C, 57.44; H, 8.31; N, 4.72.

EXAMPLE 6 1-(o-Chlorophenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol

A mixture of 35.1 g. (0.15 mole) of 1-(o-chlorophenoxy)-2-hydroxybutyl chloride, 32.6 g. (0.2 mole) of N-phenylpiperazine and 400 ml. of isopropanol was refluxed for 48 hr. The reaction mixture was allowed to stand in a refrigerator overnight and filtered. The filtrate was treated with ethereal hydrogen chloride and the salt precipitated by the addition of ether. The white crystalline solid which formed was dissolved in 0.1 mole of hydrochloric acid and then neutralized with sodium hydroxide producing a crystalline precipitate. This was recrystallized with isopropanol yielding 36 g of the free base of the product which melted at 100°-101.5° C.

Analysis: Calculated for C₂₀ H₂₅ N₂ O₂ Cl: C, 66.56; H, 6.98; N, 7.76. Found: C, 66.49; H, 7.03; N, 7.86.

The physical constants of some representative 1-aryloxy-4-amino-2-butanols made from 1-aryloxy-4-chloro-2-butanols and a selected amine by processes A, B, C and D are shown in Table I and Table II.

                                      TABLE II                                     __________________________________________________________________________     Examples 7 through 75                                                           ##STR3##                                                                       Example Number                                                                          Ar                                                                                       ##STR4##    Salt   M.P. °C.                                                                     Process                            __________________________________________________________________________      7       1-C.sub.10 H.sub.7                                                                       NHC.sub.2 H.sub.5                                                                          HCl    153-5                                                                               A                                    8       1-C.sub.10 H.sub.7                                                                       NHC.sub.6 H.sub.11                                                                         HCl    158-60                                                                              D                                    9       1-C.sub.10 H.sub.7                                                                       NOC.sub.4 H.sub.8.sup.a                                                                    --     54-6 D                                   10       1-C.sub.10 H.sub.7                                                                       NOC.sub.4 H.sub.6 (CH.sub.3).sub.2.sup.b                                                   HCl.H.sub.2 O                                                                         118-20                                                                              D                                   11       1-C.sub.10 H.sub.7                                                                       N(CH.sub.3)C.sub.6 H.sub.11                                                                --     62-5 D                                   12       1-C.sub.10 H.sub.7                                                                       NC.sub.5 H.sub.10.sup.c                                                                    HCl    135-7                                                                               D                                   13       1-C.sub.10 H.sub.7                                                                       NHCH.sub.2 C.sub.6 H.sub.5                                                                 HCl.H.sub.2 O                                                                         83-5 D                                   14       4-C.sub.6 H.sub.5C.sub.6 H.sub. 4                                                        NHCH(CH.sub.3).sub.2                                                                       HCl    190-2                                                                               B                                   15       3-CH.sub.34-ClC.sub.6 H.sub.3                                                            NHCH(CH.sub.3).sub.2                                                                       --     74-6 A                                   16       3-CF.sub.3 C.sub.6 H.sub.4                                                               NHCH(CH.sub.3).sub.2                                                                       HCl    92-4 B                                   17       2-CH.sub.35-ClC.sub.6 H.sub.3                                                            N(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5                                                        HCl    169-71                                                                              C                                   18       3-CH.sub.34-ClC.sub.6 H.sub.3                                                            NH(CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         HCl    163-5                                                                               A                                   19       2-CH.sub.34-ClC.sub.6 H.sub.3                                                            NH(CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         HCl    128-30                                                                              A                                   20       2-ClC.sub.6 H.sub.4                                                                      NHC(CH.sub.3).sub.2 CH.sub.2 OH                                                            HCl     117-119                                                                            C                                   21       C.sub.6 H.sub.5                                                                          NH(CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         HCl    143-4                                                                               D                                   22       2-CH.sub.34-ClC.sub.6 H.sub.3                                                            NC.sub.5 H.sub.94-C.sub.6 H.sub.5.sup.d                                                    HCl    148-50                                                                              D                                   23       2-CH.sub.34-ClC.sub.6 H.sub.3                                                            NC.sub.4 H.sub.8 NC.sub.6 H.sub.5                                                          di-HCl 186-8                                                                               C                                   24       2-ClC.sub.6 H.sub.4                                                                      NC.sub.5 H.sub.10.sup.c                                                                    HCl    159-60                                                                              C                                   25       3-CF.sub.3 C.sub.6 H.sub.4                                                               NH(CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         HCl    131-3                                                                               D                                   26       2-CH.sub.35-ClC.sub.6 H.sub.4                                                            NH(CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         HCl    141-3                                                                               D                                   27       3-ClC.sub.6 H.sub.4                                                                      NH(CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         HCl    154-6                                                                               D                                   28       2-CH.sub.3 OC.sub.6 H.sub.4                                                              NH(CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         --     112-14                                                                              D                                   29       C.sub.6 H.sub.5                                                                          NHCH.sub.2 C.sub.6 H.sub.5                                                                 HCl.1/2H.sub.2 O                                                                      108-10                                                                              D                                   30       2-CH.sub.3 OC.sub.6 H.sub.4                                                              NHC.sub.6 H.sub.11                                                                         H.sub.2 O                                                                             55-7 C                                   31       3-ClC.sub.6 H.sub.4                                                                      NHCH.sub.2 C.sub.6 H.sub.5                                                                 HCl    139-41                                                                              D                                   32       2-CH.sub.34-ClC.sub.6 H.sub.3                                                            NC.sub.9 H.sub.10.sup.f                                                                    HCl    149-51                                                                              D                                   33       3,5-CH.sub.3 C.sub.6 H.sub.3                                                             NH(CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         HCl.1/2H.sub.2 O                                                                      117-20                                                                              D                                   34       3,5-CH.sub.3 C.sub.6 H.sub.3                                                             NC.sub.4 H.sub.8 NC.sub.6 H.sub.5.sup.e                                                    --      88-90                                                                              D                                   35       3,5-CH.sub.3 C.sub.6 H.sub.3                                                             NC.sub.9 H.sub.10.sup.f                                                                    HCl.1/2H.sub.2 O                                                                      141-3                                                                               D                                   36       3,5-CH.sub.3 C.sub.6 H.sub.3                                                             NC.sub.5 H.sub.74-C.sub.6 H.sub.5.sup.g                                                    HCl    162-4                                                                               D                                   37       3,5-CH.sub.3 C.sub.6 H.sub.3                                                             N(CH.sub.3)C.sub.6 H.sub.11                                                                HCl    158-60                                                                              D                                   38       2-ClC.sub.6 H.sub.4                                                                      NH(CH.sub.2).sub.2 C.sub.6 H.sub.5                                                         --     92-4 D                                   39       C.sub.6 H.sub.5                                                                          NC.sub.4 H.sub.8 N2-C.sub.5 H.sub.4 N.sup.h                                                di-maleate                                                                            123-5                                                                               D                                   40       C.sub.6 H.sub.5                                                                          N(CH.sub.3)C.sub.6 H.sub.11                                                                --     50-2 D                                   41       C.sub.6 H.sub.5                                                                          N(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5                                                        maleate                                                                               118-20                                                                              D                                   42       2-CH.sub.3 OC.sub.6 H.sub.4                                                              N(CH.sub.3)C.sub.6 H.sub.11                                                                maleate                                                                               109-11                                                                              D                                   43       2-CH.sub.3 OC.sub.6 H.sub.4                                                              NOC.sub.4 H.sub.6 (CH.sub.3).sub.2                                                         --     --   D                                   44       2-CH.sub.3 OC.sub.6 H.sub.4                                                              NC.sub.4 H.sub.8 N2-C.sub.5 H.sub.4 N.sup.h                                                3 HCl.1/2H.sub.2 O                                                                    95- 7                                                                               D                                   45       2-CH.sub.3 OC.sub.6 H.sub.4                                                              NHC.sub.5 H.sub.9.sup.i                                                                    HCl    112-14                                                                              D                                   46       2-C.sub.10 H.sub.7                                                                       NC.sub.5 H.sub.74-C.sub.6 H.sub.5.sup.g                                                    HCl    168-70                                                                              C                                   47       2-C.sub.10 H.sub.7                                                                       NHCH(CH.sub.3).sub.2                                                                       --      96-98                                                                              B                                   48       4-CH.sub.3 OC.sub.6 H.sub.4                                                              N(CH.sub.3)C.sub.6 H.sub.11                                                                --     50-2 C                                   49       4-CH.sub.3 CONHC.sub.6 H.sub.4                                                           NHC.sub.6 H.sub.11                                                                         --     140-2                                                                               C                                   50       4-CH.sub.3 COC.sub.6 H.sub.4                                                             NHC.sub.6 H.sub.11                                                                         --     93-5 C                                   51       1-C.sub.10 H.sub.7                                                                       NHC(CH.sub.3).sub.2 CH.sub.2 OH                                                            --      98-100                                                                             C                                   52       3,5-CH.sub.3 C.sub.6 H.sub.3                                                             NHC.sub.10 H.sub.15.sup.j                                                                  HCl    229-31                                                                              C                                   53       5-C.sub.9 H.sub.7.sup.k                                                                  NHC.sub.6 H.sub.11                                                                         --     95-7 C                                   54       5-C.sub.9 H.sub.7                                                                        NHCH(CH.sub.3).sub.2                                                                       HCl.H.sub.2 O                                                                         103-5                                                                               C                                   55       2-CH.sub.35-ClC.sub.6 H.sub.3                                                            NHC.sub.6 H.sub.11                                                                         HCl    189-92                                                                              C                                   56       4-CH.sub.3 OC.sub.6 H.sub.4                                                              NHC.sub.10 H.sub.15.sup.j                                                                  --      78-80                                                                              C                                   57       1-C.sub.10 H.sub.7                                                                       NHC.sub.10 H.sub.15.sup.j                                                                  HCl    195-7                                                                               C                                   58       1-C.sub.10 H.sub.7                                                                       N(CH.sub.3)C.sub.8 H.sub.15                                                                HCl    143-5                                                                               C                                   59       4-CH.sub.3 OC.sub.6 H.sub.4                                                              NHCH(CH.sub.3).sub.2                                                                       HCl    118-20                                                                              C                                   60       4-CH.sub.3 OC.sub.6 H.sub.4                                                              NHC.sub.6 H.sub.11                                                                         HCl    136-8                                                                               C                                   61       5-C.sub.9 H.sub.7.sup.k                                                                  NHC(CH.sub.3).sub.2 CH.sub.2 OH                                                            --     93-5 C                                   62       5-ClC.sub.5 H.sub.3 N.sup.l                                                              NHC.sub.6 H.sub.11                                                                         HCl.H.sub.2 o                                                                         --   C                                   63       1-C.sub.10 H.sub.7                                                                       N(CH.sub.3)CH.sub.2 CH.sub.2 OH                                                            HCl    115-17                                                                              C                                   64       1-C.sub.10 H.sub.7                                                                       NHC.sub.5 H.sub.9                                                                          HCl    148-50                                                                              D                                   65       5-ClC.sub.5 H.sub.3 N.sup.l                                                              NHCH(CH.sub.3).sub.2                                                                       2HCl.H.sub.2 O                                                                        174-77                                                                              C                                   66       4-C.sub.6 H.sub.5C.sub.6 H.sub.4                                                         NHC(CH.sub.3).sub.2 CH.sub.2 OH                                                            HCl    155-57                                                                              C                                   67       2-C.sub.2 H.sub.5 OC.sub.6 H.sub.4                                                       NHCH.sub.2 C.sub.6 H.sub. 5                                                                HCl    107-7                                                                               C                                   68       2-C.sub.2 H.sub.5 OC.sub.6 H.sub.4                                                       NHC.sub.6 H.sub.11                                                                         --     83-5 C                                   69       2-C.sub.2 H.sub.5 OC.sub.6 H.sub.4                                                       NC.sub.9 H.sub.16.sup.m                                                                    HCl    140-2                                                                               C                                   70       2-C.sub.2 H.sub.5 OC.sub.6 H.sub.4                                                       NOC.sub.4 H.sub.6 (CH.sub.3).sub.2.sup.n                                                   HCl    115-17                                                                              D                                   71       1-C.sub.10 H.sub.7                                                                       NHC.sub.5 H.sub.92-CH.sub.3                                                                HCl    176-8                                                                               C                                   72       1-C.sub.10 H.sub.7                                                                       NHC.sub.6 H.sub.11                                                                         --     96-8 C                                   73       2-ClC.sub.6 H.sub.4                                                                      NHCH(CH.sub.3).sub.2                                                                       HCl     88-90                                                                              B                                   74       3,5-CH.sub.3 C.sub.6 H.sub.3                                                             NHCH(CH.sub.3).sub.2                                                                       --     69.71                                                                               B                                   75       2-CH.sub.34-ClC.sub.6 H.sub.3                                                            NHCH(CH.sub.3).sub.2                                                                       HCl     122-124                                                                            B                                   __________________________________________________________________________      .sup.a morpholino                                                              .sup.b 3,5-dimethylmorpholinyl                                                 .sup.c piperidino                                                              .sup.d 4-phenylpiperidino                                                      .sup.e 4-phenylpiperazino                                                      .sup.f 1,2,3,4-tetrahydroisoquinolyl                                           .sup.g 4-phenyl-1,2,3,6-tetrahydro-1-pyrido                                    .sup.h 4-(2-pyridyl)piperazino                                                 .sup.i cyclopentylamino                                                        .sup.j 1-adamantylamino                                                        .sup.k 2,3-dihydro-1H--inden-5-yl                                              .sup.l 5-chloro-2-pyridyl                                                      .sup.m 1-decahydroquinoline                                                    .sup.n 4-(2,6-dimethyl)morpholino.                                       

                  TABLE III                                                        ______________________________________                                         Analytical Data on Examples 7 through 75                                       Ex-                                                                            ample                                                                          Num-  Emperical    Calculated   Found                                          ber   Formula      C      H    N    C    H    N                                ______________________________________                                         7     C.sub.16 H.sub.23 ClNO.sub.2                                                                64.75  7.81 4.72 63.97                                                                               7.52 4.51                             8     C.sub.20 H.sub.28 ClNO.sub.2                                                                68.65  8.07 4.00 68.46                                                                               8.16 4.03                             9     C.sub.18 H.sub.23 NO.sub.3                                                                  71.73  7.69 4.65 71.59                                                                               7.70 4.58                             10    C.sub.20 H.sub.30 ClNO.sub.4                                                                62.57  7.88 3.65 62.51                                                                               7.68 3.73                             11    C.sub.21 H.sub.29 NO.sub.2                                                                  77.02  8.93 4.28 76.89                                                                               8.95 4.17                             12    C.sub.19 H.sub.26 ClNO.sub.2                                                                67.95  7.80 4.17 67.73                                                                               7.79 4.06                             13    C.sub.21 H.sub.26 ClNO.sub.3                                                                67.10  6.97 3.73 67.33                                                                               6.89 3.88                             14    C.sub.19 H.sub.26 ClNO.sub.2                                                                67.94  7.80 4.17 67.90                                                                               7.78 3.72                             15    C.sub.14 H.sub.22 ClNO.sub.2                                                                61.87  8.16 5.15 61.13                                                                               8.05 4.99                             16    C.sub.14 H.sub.21 NO.sub.2 F.sub.3 Cl                                                       51.30  6.46 4.27 51.24                                                                               6.42 4.41                             17    C.sub.19 H.sub.25 Cl.sub.2 NO.sub.2                                                         61.62  6.80 3.78 61.42                                                                               6.77 3.88                             18    C.sub.19 H.sub.29 Cl.sub.2 NO.sub.2                                                         61.62  6.80 3.78 61.72                                                                               6.89 3.88                             19    C.sub.19 H.sub.25 Cl.sub.2 NO.sub.2                                                         61.62  6.80 3.78 61.56                                                                               6.68 3.83                             20    C.sub.14 H.sub.23 NO.sub.3 Cl.sub.2                                                         51.86  7.15 4.32 51.85                                                                               7.17 4.40                             21    C.sub.18 H.sub.24 NO.sub.2 Cl                                                               67.17  7.52 4.35 67.22                                                                               7.56 4.31                             22    C.sub.22 H.sub.29 Cl.sub.2 NO.sub.2                                                         64.39  7.12 3.41 64.10                                                                               7.28 3.57                             23    C.sub.21 H.sub.29 Cl.sub.3 N.sub.2 O.sub.2                                                  56.32  6.53 6.25 56.07                                                                               6.47 6.24                             24    C.sub.15 H.sub.23 Cl.sub.2 NO.sub.2                                                         56.26  7.24 4.37 56.00                                                                               7.23 4.30                             25    C.sub.19 H.sub.23 ClF.sub.3 NO.sub.2                                                        58.54  5.95 3.59 58.35                                                                               6.00 3.75                             26    C.sub.19 H.sub.25 Cl.sub.2 NO.sub.2                                                         61.62  6.80 3.78 61.51                                                                               6.85 3.64                             27    C.sub.18 H.sub.23 Cl.sub.2 NO.sub.2                                                         60.68  6.51 3.93 60.75                                                                               6.58 3.96                             28    C.sub.19 H.sub.25 N.sub.1 O.sub.3                                                           72.35  7.79 4.44 72.23                                                                               7.99 4.39                             29    C.sub.34 H.sub.46 O.sub.5 Cl.sub.2 N.sub.2                                                  64.45  7.32 4.42 64.75                                                                               7.19 4.66                             30    C.sub.17 H.sub.29 NO.sub.4                                                                  65.57  9.38 4.50 65.53                                                                               8.86 4.46                             31    C.sub.17 H.sub. 21 Cl.sub.2 NO.sub.2                                                        59.67  6.18 4.09 59.62                                                                               6.23 4.11                             32    C.sub.20 H.sub.25 Cl.sub.2 NO.sub.2                                                         62.83  6.59 3.66 62.52                                                                               6.60 3.31                             33    C.sub.40 H.sub.58 Cl.sub.2 N.sub.2 O.sub.5                                                  66.93  8.14 3.90 67.19                                                                               8.03 3.76                             34    C.sub.22 H.sub.30 N.sub.2 O.sub.2                                                           74.54  8.53 7.90 74.36                                                                               8.61 8.03                             35    C.sub.44 H.sub.58 Cl.sub.2 N.sub.2 O.sub.5                                                  69.00  7.63 3.66 68.59                                                                               7.72 3.70                             36    C.sub.23 H.sub.30 NO.sub.2 Cl                                                               71.21  7.79 3.61 71.26                                                                               7.88 3.42                             37    C.sub.19 H.sub.32 NO.sub.2 Cl                                                               66.74  9.43 4.10 66.72                                                                               9.46 3.98                             38    C.sub.18 H.sub.22 N.sub.1 O.sub.2 Cl.sub.1                                                  67.60  6.93 4.38 67.28                                                                               6.96 4.37                             39    C.sub.27 H.sub.33 N.sub.3 O.sub.10                                                          57.96  5.94 7.51 57.71                                                                               5.82 7.30                             40    C.sub.17 H.sub.27 NO.sub.2                                                                  73.61  9.81 5.05 73.32                                                                               9.64 4.94                             41    C.sub.22 H.sub.27 NO.sub.6                                                                  65.82  6.78 3.49 65.84                                                                               6.77 3.42                             42    C.sub.22 H.sub.33 NO.sub.7                                                                  62.39  7.85 3.31 62.15                                                                               7.68 3.15                             43    C.sub.17 H.sub.27 NO.sub.4                                                                  65.99  8.80 4.53 65.15                                                                               8.77 4.33                             44    C.sub.20 H.sub.35 Cl.sub.3 N.sub.3 O.sub.4                                                  49.24  7.23 8.61 49.18                                                                               6.99 8.85                             45    C.sub.16 H.sub.26 ClNO.sub.3                                                                60.85  8.30 4.43 60.71                                                                               8.12 4.34                             46    C.sub.25 H.sub.28 ClNO.sub.2                                                                73.25  6.88 3.42 72.59                                                                               6.99 3.43                             47    C.sub.17 H.sub.23 NO.sub.2                                                                  74.69  8.48 5.12 74.21                                                                               8.50 5.02                             48    C.sub.18 H.sub.29 NO.sub.3                                                                  70.32  9.51 4.56 70.15                                                                               9.41 4.56                             49    C.sub.18 H.sub.28 N.sub.2 O.sub.3                                                           67.47  8.81 8.74 67.35                                                                               8.75 8.65                             50    C.sub.18 H.sub.27 NO.sub.3                                                                  70.79  8.91 4.59 70.71                                                                               8.91 4.76                             51    C.sub.18 H.sub.25 NO.sub.3                                                                  71.26  8.30 4.62 71.34                                                                               8.23 4.46                             52    C.sub.22 H.sub.34 ClNO.sub.2                                                                69.54  9.02 3.69 69.26                                                                               8.95 3.73                             53    C.sub.19 H.sub.29 NO.sub.2                                                                  75.21  9.63 4.62 75.04                                                                               9.55 4.60                             54    C.sub.18 H.sub.28 ClNO.sub.3                                                                60.46  8.88 4.41 59.81                                                                               8.05 4.47                             55    C.sub.17 H.sub.26 ClNO.sub.2                                                                58.79  7.55 4.03 58.54                                                                               7.70 3.93                             56    C.sub.21 H.sub.32 NO.sub.4                                                                  69.58  8.90 3.86 69.29                                                                               8.89 4.20                             57    C.sub.24 H.sub.35 ClNO.sub.4                                                                65.96  8.07 3.20 66.31                                                                               7.85 3.25                             58    C.sub.23 H.sub.34 ClNO.sub.2                                                                70.48  8.73 3.57 69.98                                                                               8.64 3.45                             59    C.sub.14 H.sub.24 ClNO.sub.3                                                                58.02  8.35 4.83 57.68                                                                               8.27 4.81                             60    C.sub.17 H.sub.28 ClNO.sub.3                                                                61.90  8.56 4.25 61.37                                                                               8.44 4.01                             61    C.sub.17 H.sub.25 NO.sub.3                                                                  69.59  9.27 4.77 69.66                                                                               9.24 4.65                             62    C.sub.15 H.sub.20 Cl.sub.2 NO.sub.2                                                         51.00  7.42 7.93 51.19                                                                               7.32 8.02                             63    C.sub.17 H.sub.24 ClNO.sub.3                                                                62.67  7.42 4.30 62.58                                                                               7.40 4.20                             64    C.sub.19 H.sub.26 ClNO.sub.2                                                                67.94  7.80 4.17 67.76                                                                               7.78 4.21                             65    C.sub.12 H.sub.23 Cl.sub.3 N.sub.2 O.sub.3                                                  41.22  6.63 8.01 42.27                                                                               6.27 8.09                             66    C.sub.20 H.sub.28 ClNO.sub.3                                                                65.65  7.71 3.83 65.37                                                                               7.67 3.75                             67    C.sub.19 H.sub.26 ClNO.sub.3                                                                64.86  7.45 3.98 64.83                                                                               7.35 4.23                             68    C.sub.18 H.sub.29 NO.sub.3                                                                  70.32  9.51 4.56 70.40                                                                               9.58 4.59                             69    C.sub.21 H.sub.34 ClNO.sub.3                                                                65.69  8.93 3.65 65.78                                                                               8.77 3.60                             70    C.sub.18 H.sub.30 ClNO.sub.4                                                                60.07  8.40 3.89 60.04                                                                               8.28 3.81                             71    C.sub.20 H.sub.28 NO.sub.2 Cl                                                               68.65  8.06 4.00 68.28                                                                               8.06 3.85                             72    C.sub.18 H.sub.24 NO.sub.2 Cl                                                               64.53  8.12 4.70 64.40                                                                               8.17 4.55                             73    C.sub.13 H.sub.21 Cl.sub.2 NO.sub.2                                                         53.07  7.19 4.61 53.91                                                                               7.36 4.82                             74    C.sub.15 H.sub.25 NO.sub.2                                                                  71.67  10.02                                                                               5.57 71.65                                                                               10.11                                                                               5.34                             75    C.sub.14 H.sub.23 Cl.sub.2 NO.sub.2                                                         54.55  7.52 4.54 54.48                                                                               7.52 4.29                             ______________________________________                                    

EXAMPLE 76 1-(2-Methoxyphenoxy)-4-phthalimido-2-butanol

A mixture of 24.6 g. (0.1 mole) of 1-(2-methoxyphenoxy)-4-chloro-2-butanol, 18.5 g. (0.1 mole) of potassium phthalimido, 150 ml. of dimethylformamide and 150 ml. of toluene was refluxed for 8 hours. The cooled filtered solution was diluted with 500 ml. of water, the toluene layers separated and washed with water until the washings were neutral. The product separated from the washed toluene solution as a crystalline solid which was recrystallized from acetone. The recrystallized material melted at 108°-110° C.

Analysis: Calcd. for C₁₉ H₁₉ NO₅ : C, 66.94; H, 5.61; N, 4.10. Found: C, 66.94; H, 5.74; N, 4.15.

EXAMPLE 77 1-(2-Ethoxyphenoxy)-4-phthalimido-2-butanol

A mixture of 30 g. (0.12 mole) of 1-(2-ethoxyphenoxy)-4-chloro-2-butanol and 18.5 g. (0.10 mole) of potassium phthalimide was heated slowly to 130° C. for 10 min. and at 160° C. for one hour with stirring. The reaction mixture was extracted with 250 ml. of hot toluene. A crystalline solid separated from the toluene extract when cooled to room temperature. The solid was recrystallized from toluene and melted at 93°-95° C.

Analysis: Calcd. for C₂₀ H₂₁ NO₅ : C, 67.59; H, 5.96; N, 3.94. Found: C, 67.78; H, 6.03; N, 4.06.

EXAMPLE 78 1-Phenoxy-4-(4-phenyl-1-piperazinyl)-2-butanol

A mixture of 6.5 g (0.04 mole) of 1-phenylpiperazine, 8.4 g (0.042 mole) of 4-chloro-1-phenoxy-2-butanol and 15.9 g (0.15 mole) of anhydrous sodium carbonate in 200 ml of 1-butanol was heated at reflux 20 hr. The mixture was concentrated under reduced pressure and the residue was partitioned between water and benzene. The benzene layer was washed with water and aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to give the title product in the residue which was recrystallized from isopropyl alcohol to give 8.9 g (68%) of white powder, m.p. 93°-94° C.

Analysis: Calculated for C₂₀ H₂₆ N₂ O₂ : C, 73.59; H, 8.03; N, 8.58. Found: C, 73.48; H, 8.09; N, 8.56.

EXAMPLE 79 1-(4-Chlorophenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 3.2 g (0.02 mole) of 1-phenylpiperazine, 4.9 g (0.021 mole) of 4-chloro-1-(4-chlorophenoxy)-2-butanol and 8.0 g (0.075 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 3.8 g (53%) of white powder, m.p. 83°-85° C. Recrystallizing solvent used was isopropyl alcohol.

Analysis: Calculated for C₂₀ H₂₅ ClN₂ O₂ : C, 66.57; H, 6.98; N, 7.76. Found: C, 66.65; H, 7.08; N, 7.69.

EXAMPLE 80 1-(2-Methoxyphenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 3.2 g (0.02 mole) of 1-phenylpiperazine, 4.8 g (0.02 mole) of 4-chloro-1-(2-methoxyphenoxy)-2-butanol and 8.0 g (0.075 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 4.5 g (64%) of white powder, m.p. 101°-102° C. Recrystallizing solvent used was iropropyl alcohol.

Analysis: Calculated for C₂₁ H₂₈ N₂ O₃ : C, 70.76; H, 7.92; N, 7.86. Found: C, 70.47; H, 8.04; N, 7.76.

EXAMPLE 81 1-(4-Chloro-3-methylphenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 2.4 g (0.015 mole) of 1-phenylpiperazine, 3.7 g. (0.015 mole) of 4-chloro-1-(4-chloro-3-methylphenoxy)-2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 3.6 g (64%) of white solid, 102°-103° C. Recrystallizing solvent used was isopropyl alcohol.

Analysis: Calculated for C₂₁ H₂₇ ClN₂ O₂ : C, 67.28; H, 7.26; N, 7.47. Found: C, 67.42; H, 7.35; N, 7.37.

EXAMPLE 82 1-(4-Phenyl-phenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 2.4 g (0.015 mole) of 4-chloro-1-[4-(1,1'-biphenyl)yloxy]-2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 3.7 g (62%) of white solid, m.p. 101°-106° C. Recrystallizing solvent used was isopropyl alcohol.

Analysis: Calculated for C₂₆ H₃₀ N₂ O₂ : C, 77.58; H, 7.51; N, 6.96. Found: C, 77.33; H, 7.55; N, 6.74.

EXAMPLE 83 1-Phenoxy-4-[4-(4-fluorophenyl)-1-piperazinyl]-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 3.6 g (0.02 mole) of 1-(4-fluorophenyl)piperazine, 4.0 g (0.02 mole) of 4-chloro-1-phenoxy 2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 5.1 g (74%) of off-white powder, m.p. 97°-99° C. Recrystallizing solvent used was isopropyl alcohol.

Analysis: Calculated for C₂₀ H₂₅ FN₂ O₂ : C, 69.75; H, 7.32; N, 8.13. Found: C, 69.78; H, 7.34; N, 8.06.

EXAMPLE 84 1-(3-Trifluoromethylphenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 2.4 g (0.015 mole) of 1-phenylpiperazine, 4.0 g (0.015 mole) of 4-chloro-1-(3-trifluoromethylphenoxy)-2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 2.5 g (42%) of a tan powder, m.p. 73°-74° C. Recrystallizing solvent used was ligroin.

Analysis: Calculated for C₂₁ H₂₅ F₃ N₂ O₂ : C, 63.95; H, 6.39; N, 7.10. Found: C, 63.87; H, 6.41; N, 6.99.

EXAMPLE 85 1-Phenoxy-4-[4-(4-methoxyphenyl)-1-piperazinyl]-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 4.8 g (0.025 mole) of 1-(4-methoxyphenyl)piperazine, 5.0 g (0.025 mole) of 4-chloro-1-phenoxy-2-butanol and 8.0 g (0.075 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 6.4 g (72%) of tan towder., m.p. 95°-97° C. Recrystallizing solvent used was isopropyl alcohol.

Analysis: Calculated for C₂₁ H₂₈ N₂ O₃ : C, 70.76; H, 7.92; N, 7.86. Found: C, 70.43; H, 7.89; N, 7.68.

EXAMPLE 86 1-Phenoxy-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 2.9 g (0.015 mole) of 1-(2-methoxyphenyl)piperazine (95%), 3.0 g (0.015 mole) of 4-chloro-1-phenoxy-2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 4.0 g (75%) of off-white powder, m.p. 74°-76° C. Recrystallizing solvent used was isopropyl alcohol.

Analysis: Calculated for C₂₁ H₂₈ H₂ O₃ : C, 70.76; H, 7.92; N, 7.86. Found: C, 70.72; H, 7.88; N, 7.78.

EXAMPLE 87 1-Phenoxy-4-[4-(4-chlorophenyl)-1-piperazinyl]-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 3.0 g (0.015 mole) of 1-(p-chlorophenyl)piperazine, 3.0 g (0.015 mole) of 4-chloro-1-phenoxy-2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 3.8 g (70%) of off-white powder, m.p. 108°-110° C. Recrystallizing solvent used was isopropyl alcohol.

Analysis: Calculated for C₂₀ H₂₅ ClN₂ O₂ : C, 66.57; H, 6.98; N, 7.76. Found: C, 66.60; H, 7.10; N, 7.72.

EXAMPLE 88 1-Phenoxy-4-[4-(3-methoxyphenyl)-1-piperazinyl]-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 3.8 g (0.02 mole) of 1-(3-methoxyphenyl)piperazine, 4.0 g (0.02 mole) of 4-chloro-1-phenoxy-2-butanol and 8.0 g (0.075 mole) of anhydrous sodium carbonate in 150 ml of 1-butanol gave 3.3 g (45%) of off-white powder, m.p. 58°-60° C. Recrystallizing solvent used was diethyl ether-petroleum ether.

Analysis: Calculated for C₂₁ H₂₈ N₂ O₃ : C, 70.76; H, 7.92; N, 7.86. Found: C, 70.66; H, 8.00; N, 7.82.

EXAMPLE 89 1-Phenoxy-4-[4-(3-trifluoromethylphenyl)-1-piperazinyl] 2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 3.5 g (0.015 mole) of N-(α,α,α-trifluoro-m-tolyl)piperazine, 3.0 g (0.015 mole) of 4-chloro-1-phenoxy-2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 3.9 g (66%) of white powder, m.p. 83°-84° C. The recrystallizing solvent used was isopropyl alcohol.

Analysis: Calculated for C₂₁ H₂₅ F₃ N₂ O₂ : C, 63.95; H, 6.39; N, 7.10. Found: C, 64.10; H, 6.46; N, 7.09.

EXAMPLE 90 1-Phenoxy-4-[4-(3-chlorophenyl)-1-piperazinyl]-2-butanol

The compound was prepared according to the procedure of Example 78. A mixture of 3.0 g (0.015 mole) of 1-(3-chlorophenyl)piperazine, 3.0 g (0.015 mole) of 4-chloro-1-phenoxy-2-butanol, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 100 ml of 1-butanol gave 3.7 g (69%) of white powder, m.p. 76°-78° C. The recrystallizing solvent used was isopropyl alcohol.

Analysis: Calculated for C₂₀ H₂₅ ClN₂ O₂ : C, 66.57; H, 6.98; N, 7.76. Found: C, 66.47; H, 6.97; N, 7.72.

EXAMPLE 91 1-Phenoxy-4-[4-(2-chlorophenyl)-1-piperazinyl]-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 3.0 g (0.015 mole) of 1-(2-chlorophenyl)piperazine, 3.0 g (0.015 mole) of 4-chloro-1-phenoxy-2-butanol, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 100 ml of 1-butanol gave an oil as residue. The oil was purified by chromatography on 75 g of silica gel to yield 1.3 g (24%) of white powder, m.p. 53°-55° C. The recrystallizing solvent was diethyl ether.

Analysis: Calculated for C₂₀ H₂₅ ClN₂ O₂ : C, 66.57; H, 6.98; N, 7.76. Found: C, 66.96; H, 7.03; N, 7.69.

EXAMPLE 92 1-(4-Chlorophenoxy)-4-[4-(4-fluorophenyl)-1-piperazinyl]-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 1.8 g (0.01 mole) of 1-(4-fluorophenyl)-piperazine, 2.4 g (0.01 mole) of 4-chloro-1-(4-chlorophenoxy)-2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 1.4 g (37%) of white powder, m.p. 90°-92° C. The recrystallizing solvent used was isopropyl ether.

Analysis: Calculated for C₂₀ H₂₄ ClFN₂ O₂ : C, 63.40; H, 6.39; N, 7.39. Found: C, 63.76; H, 6.49; N, 7.31.

EXAMPLE 93 1-Phenoxy-4-[4-(3,4-dichlorophenyl)-1-piperazinyl]-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 2.3 g (0.01 mole) of 1-(3,4-dichlorophenyl)piperazine, 2.0 g (0.01 mole) of 4-chloro-1-phenoxy-2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 2.5 g (63%) of off-white powder, m.p. 120.5°-121.5° C. The recrystallizing solvent was isopropyl alcohol.

Analysis: Calculated for C₂₀ H₂₄ Cl₂ N₂ O₂ : C, 60.76; H, 6.12; N, 7.09. Found: C, 60.71; H, 6.19; N, 7.07.

EXAMPLE 94 1-Phenoxy-4-[4-(4-methylphenyl)-1-piperazinyl]-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 1.8 g (0.01 mole) of 1-(4-methylphenyl)piperazine, 2.2 g (0.01 mole) of 4-chloro-1-phenoxy-2-butanol and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 2.1 g (62%) of off-white powder, m.p. 90°-92° C. The recrystallizing solvent used was isopropyl alcohol.

Analysis: Calculated for C₂₁ H₂₈ N₂ O₂ : C, 74.08; H, 8.29; N, 8.23. Found: C, 74.43; H, 8.38; N, 8.22.

EXAMPLE 95 1-Phenoxy-4-[4-(4-bromophenyl)-1-piperazinyl]-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 2.4 g (0.01 mole) of the base of 1-(4-bromophenyl)-piperazine, 2.0 g (0.01 mole) of 4-chloro-1-phenoxy-2-butanol, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave 3.0 g (73%) of white powder, m.p. 125°-126° C. The recrystallizing solvent used was isopropyl alcohol.

Analysis: Calculated for C₂₀ H₂₅ BrN₂ ₂ : C, 59.27; H, 6.22; N, 6.91. Found: C, 58.96; H, 6.22; N, 7.03.

EXAMPLE 96 1-Phenoxy-4-[4-(4-acetylphenyl)-1-piperazinyl]-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 2.0 g (0.01 mole) of 4-(1-piperazino)acetophenone, 2.0 g (0.01 mole) of 4-chloro-1-phenoxy-2-butanol, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave 3.0 g (81%) of pale yellow solid, m.p. 113.5°-117° C. The recrystallizing solvent was isopropyl alcohol.

Analysis: Calculated for C₂₂ H₂₈ N₂ O₃ : C, 71.71; H, 7.66; N, 7.60. Found: C, 71.95; H, 7.70; N, 7.55.

EXAMPLE 97 1-(4-Bromophenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol

A mixture of 8.4 g (0.03 mole) of 1-(4-bromophenoxy)-4-chloro-2-butanol, 4.9 g (0.03 mole) of 1-phenylpiperazine, 16.0 g (0.15 mole) of sodium carbonate, and 0.3 g (0.002 mole) of potassium iodide in a total volume of 200 ml of 1 butanol was heated at reflux with stirring for 16 hr. The suspended solids were collected by filtration and the hot filtrate was concentrated under reduced pressure to give a golden oil as residue. The oil was partitioned between cold 10% sodium hydroxide solution and benzene. The benzene layer was washed three times with 50 ml portions of water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give an oil that crystallized when triturated with petroleum ether (30°-60° b.p. range). The solid was recrystallized from ethyl ether and then from ethanol-benzene to give 4.3 g (35%) of white solid, m.p. 100°-103° C.

Analysis: Calculated for C₂₀ H₂₅ BrN₂ O₂ : C, 59.26; H, 6.22; N, 6.91. Found: C, 59.25; H, 6.29; N, 6.91.

EXAMPLE 98 1-(4-Methylphenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol

This compound was prepared according to the procedure of Example 97. A mixture of 6.5 g (0.03 mole) of 4-chloro-1-(4-methylphenoxy)-2-butanol, 4.9 g (0.03 mole) of 1-phenylpiperazine, 16.0 g (0.15 mole) of anhydrous sodium carbonate, and 0.3 g (0.002 mole) of potassium iodide in a total volume of 200 ml of 1-butanol gave 6.4 g (63%) of white solid, m.p. 123°-125° C. The recrystallizing solvent used was a mixture of benzene and petroleum ether.

Analysis: Calculated for C₂₁ H₂₈ N₂ O₂ : C, 74.08; H, 8.29; N, 8.23. Found: C, 73.91; H, 8.32; N, 8.18.

EXAMPLE 99 1-(4-Fluorophenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol

This compound was prepared according to the procedure of Example 97. A mixture of 6.6 g (0.03 mole) of 4-chloro-1-(4-fluorophenoxy)-2-butanol, 4.9 g (0.03 mole) of 1-phenylpiperazine, 16.0 g (0.15 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in a total volume of 200 ml of 1-butanol gave 5.5 g (53%) of white solid, m.p. 71°-73° C. The recrystallizing solvent used was a mixture of benzene and petroleum ether.

Analysis: Calculated for C₂₀ H₂₅ FN₂ O₂ : C, 69.74; H, 7.32; N, 8.13. Found: C, 69.70; H, 7.33; N, 8.09.

EXAMPLE 100 1-(4-Cyanophenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol dihydrochloride

This compound was prepared according to the procedure of Example 97. A mixture of 6.8 g (0.03 mole) of 4-chloro-1-(4-cyanophenoxy)-2-butanol, 4.9 g (0.03 mole) of 1-phenylpiperazine, 16.0 g (0.15 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in a total volume of 200 ml of 1-butanol gave an oil as residue. The hydrochloric acid salt was formed in ethereal hydrogen chloride and the collected solid was recrystallized from methanolethyl ether to give 3.7 g (35%) of white solid, m.p. 195°-198° C.

Analysis: Calculated for C₂₁ H₂₇ Cl₂ N₃ O₂ : C, 59.44; H, 6.41; N, 9.90. Found: C, 59.69; H, 6.48; N, 9.89.

EXAMPLE 101 1-(4-Methoxyphenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol

This compound was prepared according to the procedure of Example 97. A mixture of 6.9 g (0.03 mole) of 4-chloro-1-(4-methoxyphenoxy)-2-butanol, 4.9 g (0.03 mole) of 1-phenylpiperazine, 16.0 g (0.15 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in a total volume of 200 ml of 1-butanol gave an oil which solidified. The collected solid was recrystallized from 2-propanol to give 2.9 g (27%) of white crystalline powder, m.p. 103°-105° C.

Analysis: Calculated for C₂₁ H₂₈ N₂ O₂ : C, 70.76; H, 7.92; N, 7.86. Found: C, 70.66; H, 7.94; N, 7.81.

EXAMPLE 102 1-(3,4-Dichlorophenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol dihydrochloride

This compound was prepared according to the procedure of Example 97. A mixture of 8.1 g (0.03 mole) of 4-chloro-1-(3,4-dichlorophenoxy)-2-butanol, 4.9 g (0.03 mole) of 1-phenylpiperazine, 16.0 g (0.15 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in a total volume of 200 ml of 1-butanol gave a golden oil as residue. The hydrochloric acid salt was formed in ethereal hydrogen chloride and the collected solid was recrystallized from methanol-ethyl ether to give 5.1 g (37%) of white solid, m.p. 210°-213° C.

Analysis: Calculated for C₂₀ H₂₆ Cl₄ N₂ O₂ : C, 51.30; H, 5.60; N, 5.98. Found: C, 51.53; H, 5.63; N, 6.01.

EXAMPLE 103 1-(4-Nitrophenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol dihydrochloride

This compound was prepared according to the procedure of Example 97. A mixture of 12.3 g (0.05 mole) of 4-chloro-1-(4-nitrophenoxy)-2-butanol, 8.1 g (0.05 mole) of 1-phenylpiperazine, and 26.0 g (0.25 mole) of anhydrous sodium carbonate in a total volume of 250 ml of 1-butanol gave a golden oil as residue. The hydrochloride was formed in ethereal hydrogen chloride and the collected solid was recrystallized thrice from methanol-water to give 1.1 g (5%) of white solid, m.p. 195°-200° C.

Analysis: Calculated for C₂₀ H₂₇ Cl₂ N₃ O₄ : C, 54.06; H, 6.13; N, 9.46. Found: C, 54.03; H, 6.14; N, 9.48.

EXAMPLE 104 1-(4-Chlorophenoxy)-4-[4-(2-pyridyl)-1-piperazinyl]-2-butanol dihydrochloride

This compound was prepared according to the procedure of Example 97. A mixture of 5.0 g (0.03 mole) of 1-(2-pyridyl)piperazine, 7.0 g (0.03 mole) of 4-chloro-1-(4-chlorophenoxy)-2-butanol, 16.0 g (0.15 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in a total volume of 200 ml of 1-butanol gave a golden oil as residue. The hydrochloride was formed in 2-propanol saturated with hydrogen chloride and the collected solid was recrystallized from aqueous 2-propanol to give 8.1 g (62%) of white solid, m.p. >245° C.

Analysis: Calculated for C₁₉ H₂₆ Cl₃ N₃ O₂ : C, 52.49; H, 6.03; N, 9.66. Found: C, 52.43; H, 6.09; N, 9.70.

EXAMPLE 105 1-(4-Aminoacetylphenoxy)-4-(4-phenylpiperazino)-2-butanol monohydrochloride

This compound was prepared according to the procedure of Example 97. A mixture of 7.3 g (0.03 mole) of 4-(4-chloro-2-hydroxybutoxy)benzamide, 5.0 g (0.03 mole) of 1-phenylpiperazine, 16.0 g (0.15 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in a total volume of 200 ml of 1-butanol gave a cream colored semi-solid as residue. The hydrochloric acid salt was formed in 2-propanol saturated with hydrogen chloride, and the collected solid was recrystallized from methanol-water to give 4.8 g (40%) of white solid, m.p. 238°-241° C.

Analysis: Calculated for C₂₁ H₂₈ ClN₃ O₃ : C, 62.14; H, 6.95; N, 10.35. Found: C, 62.11; H, 6.96; N, 10.36.

EXAMPLE 106 1-(4-Tertiarybutylphenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol monohydrochloride

This compound was prepared according to the procedure of Example 97. A mixture of 7.7 g (0.03 mole) of 4-chloro-1-[4-(1,1-dimethylethyl)phenoxy]-2-butanol, 5.0 g (0.03 mole) of 1-phenylpiperazine, 16.0 g (0.15 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in a total volume of 200 ml of 1-butanol gave a golden oil as residue. The hydrochloric acid salt was formed in 2-propanol saturated with hydrogen chloride, and the collected solid was recrystallized from 2-propanolmethanol-water to give 6.0 g (48%) of white, crystalline solid, m.p. 190°-193° C.

Analysis: Calculated for C₂₄ H₃₅ ClN₂ O₂ : C, 68.80; H, 8.42; N, 6.69. Found: C, 68.78; H, 8.45; N, 6.68.

EXAMPLE 107 1-(4-Fluorophenoxy)-4-[4-(4-fluorophenyl)-1-piperazinyl]-2-butanol monohydrochloride

This compound was prepared according to the procedure of Example 97. A mixture of 6.5 g (0.03 mole) of 4-chloro-1-(4-fluorophenoxy)-2-butanol, 5.4 g (0.03 mole) of 1-(4-fluorophenyl)piperazine, 16.0 g (0.15 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in a total volume of 200 ml of 1-butanol gave a golden oil as residue. The hydrochloric acid salt was formed in 2-propanol saturated with hydrogen chloride, and the collected solid was recrystallized from methanol-water-ethyl ether to give 6.7 g (56%) of white solid, m.p. 161°-165° C.

Analysis: Calculated for C₂₀ H₂₅ ClF₂ N₂ O₂ : C, 60.22; H, 6.32; N, 7.02. Found: C, 59.87; H, 6.29; N, 6.97.

EXAMPLE 108 1-(4-Acetylphenoxy)-4-(4-phenyl-1-piperazinyl)-2-butanol dihydrochloride

This compound was prepared according to the procedure of Example 97. A mixture of 7.3 g (0.03 mole) of 1-[4-(4-chloro-2-hydroxybutoxy)phenyl]ethanone, 5.0 g (0.03 mole) of 1-phenylpiperazine, 16.0 g (0.15 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in a total volume of 200 ml of 1-butanol gave a brown oil as residue. The hydrochloric acid salt was formed in 2-propanol saturated with hydrogen chloride, and the collected solid was recrystallized from 95% ethanol to give 5.6 g (42%) of pale yellow solid, m.p. 203°-208° C.

Analysis: Calculated for C₂₂ H₃₀ Cl₂ N₂ O₃ : C, 59.87; H, 6.85; N, 6.35. Found: C, 59.86; H, 7.01; N, 6.32.

EXAMPLE 109 1-(4-Fluorophenoxy)-4-[4-(2-pyridinyl)-1-piperazinyl]-2-butanol dihydrochloride

This compound was prepared according to the procedure of Example 97. A mixture of 6.6 g (0.03 mole) of 4-chloro-1-(4-fluorophenoxy)-2-butanol, 4.9 g (0.03 mole) of 1-(2-pyridyl)piperazine, 16.0 g (0.15 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in a total volume of 200 ml of 1-butanol gave a golden oil as residue. The hydrochloride was formed in 2-propanol saturated with hydrogen chloride and the collected solid was recrystallized from methanol/water to give 9.0 g (72%) of white solid, m.p. >245° C.

Analysis: Calculated for C₁₉ H₂₆ Cl₂ FN₃ O₂ : C, 54.55; H, 6.27; N, 10.04. Found: C, 54.57; H, 6.34; N, 10.16.

EXAMPLE 110 1-(4-Fluorophenoxy)-4-[4-(2-pyridinyl)-1-piperazinyl]-2-butanol

A mixture of 9.0 g (0.0413 mole) of 4-chloro-1-(4-fluorophenoxy)-2-butanol, 6.8 g (0.0414 mole) of 1-(2-pyridinyl)piperazine, 14.5 g (0.1374 mole) of anhydrous sodium carbonate and 0.24 g of potassium iodide in 200 ml of 1-butanol was heated at reflux for 20 hr. The mixture was concentrated under reduced pressure and the residue was partitioned between 200 ml of water and 200 ml of benzene. The benzene layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give a thick yellow oil. Upon trituration with petroleum ether (30°-60° C.), the oil solidified. The collected solid was recrystallized from ligroin to yield 8.2 g (57%) of white, crystalline solid, m.p. 72°-73° C.

Analysis: Calculated for C₁₉ H₂₄ FN₃ O₂ : C, 66.07; H, 7.00; N, 12.17. Found: C, 66.05; H, 7.11; N, 12.31.

EXAMPLE 111 1-(4-Fluorophenoxy)-4-[4-(4-methylphenyl)-1-piperazinyl]-2-butanol dihydrochloride

This compound was prepared according to the procedure of Example 97. A mixture of 1.8 g (0.01 mole) of 1-(4-methylphenyl)piperazine, 2.2 g (0.01 mole) of 4-chloro-1-(4-fluorophenoxy)-2-butanol, 5.2 g (0.05 mole) of anhydrous sodium carboate, and 0.1 g of potassium iodide in a total volume of 200 ml of 1-butanol gave a golden oil as residue. The hydrochloride was formed in 2-propanol saturated with hydrogen chloride and the collected solid was recrystallized from methanol-water-ethyl ether to give 1.8 g (41%) of white solid, m.p. 200°-205° C.

Analysis: Calculated for C₂₁ H₂₉ Cl₂ FN₂ O₂ : C, 58.47; H, 6.78; N, 6.49. Found: C, 58.67; H, 6.82; N, 6.54.

EXAMPLE 112 1-(4-Chloro-3-methylphenoxy)-4-[4-(4-fluorophenyl)-1-piperazinyl]-2-butanol

This compound was prepared according to the procedure of Example 97. A mixture of 1.8 g (0.01 mole) of 1-(4-fluorophenyl)piperazine, 2.5 g (0.01 mole) of 4-chloro-1-(4-chloro-3-methylphenoxy)-2-butanol, 5.2 g (0.05 mole) of anhydrous sodium carbonate and 0.1 g of potassium iodide in a total volume of 200 ml of 1-butanol gave a golden oil as residue. The hydrochloride was formed in 2-propanol saturated with hydrogen chloride and the collected solid was recrystallized from methanol-water-ethyl ether to give 1.7 g (36%) of white solid, m.p. 199°-203° C.

Analysis: Calculated for C₂₁ H₂₈ Cl₃ FN₂ O₂ : C, 54.15; H, 6.06; N, 6.01. Found: C, 54.48; H, 6.20; N, 6.07.

EXAMPLE 113 1-(4-Chlorophenoxy)-4-[4-(4-chlorophenyl)-1-piperazinyl]-2-butanol dihydrochloride

This compound was prepared according to the procedure of Example 97. A mixture of 3.2 g (0.016 mole) of 1-(4-chlorophenyl)piperazine, 3.8 g (0.016 mole) of 4-chloro-1-(4-chlorophenoxy)-2-butanol, 8.3 g (0.078 mole) of anhydrous sodium carbonate and 0.1 g of potassium iodide in a total volume of 200 ml of 1-butanol gave a golden oil as residue. The hydrochloride was formed in 2-propanol saturated with hydrogen chloride and the collected solid was recrystallized from methol-water-ethyl ether to give 3.6 g (47%) of white solid, m.p. 195°-200° C.

Analysis: Calculated for C₂₀ H₂₆ Cl₄ N₂ O₂ : C, 51.30; H, 5.60; N, 5.98. Found: C, 51.57; H, 5.70; N, 6.07.

EXAMPLE 114 1-(4-Fluorophenoxy)-4-[4-(4-chlorophenyl)-1-piperazinyl]-2-butanol monohydrochloride monohydrate

This compound was prepared according to the procedure of Example 97. A mixture of 3.2 g (0.016 mole) of 1-(4-chlorophenyl)piperazine, 3.6 g (0.016 mole) of 4-chloro-1-(4-fluorophenoxy)-2-butanol, 8.3 g (0.078 mole) of anhydrous sodium carbonate and 0.1 g of potassium iodide in a total volume of 200 ml of 1-butanol gave a golden oil as residue. The hydrochloride was formed in 2-propanol saturated with hydrogen chloride and the collected solid was recrystallized from methanol-water-ethyl ether to give 2.9 g (40%) of white solid, m.p. 183°-186° C.

Analysis: Calculated for C₂₀ H₂₇ Cl₂ FN₂ O₃ : C, 55.43; H, 6.28; N, 6.46. Found: C, 55.13; H, 5.99; N, 6.49.

EXAMPLE 115 1-(4-Chlorophenoxy)-4-[4-(4-methylphenyl)-1-piperazinyl]-2-butanol monohydrochloride sesquihydrate

This compound was prepared according to the procedure of Example 97. A mixture of 1.8 g (0.01 mole) of 1-(4-methylphenyl)piperazine, 2.4 g (0.01 mole) of 4-chloro-1-(4-chlorophenoxy)-2-butanol, 5.2 g (0.05 mole) of anhydrous sodium carbonate and 0.1 g of potassium iodide in a total volume of 200 ml of 1-butanol gave a golden oil as residue. The hydrochloride was formed in 2-propanol saturated with hydrogen chloride and the collected solid was recrystallized from ethanol-water-ethyl ether to give 1.4 g (31%) of white solid, m.p. 190°-195° C.

Analysis: Calculated for C₂₁ H₂₈ Cl₂ N₂ O₂.1.5H₂ O: C, 57.54; H, 7.13; N, 6.39. Found: C, 57.67; H, 6.71; N, 6.40.

EXAMPLE 116 1-(4-Chloro-3-methylphenoxy)-4-[4-(2-pyridl)-1-piperazinyl]-2-butanol dihydrochloride

This compound was prepared according to the procedure of Example 97. A mixture of 1.6 (0.01 mole) of 1-(2-pyridyl)piperazine, 2.5 g (0.01 mole) of 4-chloro-1-(4-chloro-3-methylphenoxy)-2-butanol, 5.2 g (0.05 mole) of anhydrous sodium carbonate and 0.1 g of potassium iodide in a total volume of 200 ml of 1-butanol gave a golden oil as residue. The hydrochloride was formed in 2-propanol saturated with hydrogen chloride and the collected solid was recrystallized from methanol-water-ethyl ether to give 2.9 g (65%) of white solid, m.p. >250° C.

Analysis: Calculated for C₂₀ H₂₈ Cl₃ N₃ O₂ : C, 53.53; H, 6.29; N, 9.36. Found: C, 53.50; H, 6.33; N, 9.38.

EXAMPLE 117 1-(4-Chlorophenoxy)-4-[4-(4-methoxyphenyl)-1-piperazinyl]-2-butanol dihydrochloride

This compound was prepared according to the procedure of Example 97. A mixture of 3.0 g (0.015 mole) of 1-(4-methoxyphenyl)-piperazine, 3.7 g (0.015 mole) of 4-chloro-1-(4-chlorophenoxy)-2-butanol, 5.2 g (0.05 mole) of anhydrous sodium carbonate and 0.1 g of potassium iodide in a total volume of 200 ml of 1-butanol gave an oil as residue. The hydrochloride was formed in 2-propanol saturated with hydrogen chloride and the collected solid was recrystallized from methanol-water to give 3.3 g (42%) of white, crystalline solid, m.p. 220°-225° C.

Analysis: Calculated for C₂₁ H₂₉ Cl₃ N₂ O₃ : C, 54.38; H, 6.30; N, 6.04. Found: C, 54.37; H, 6.31; N, 6.07.

EXAMPLE 118 1-(4-Fluorophenoxy)-4-[4-(4-methoxyphenyl)-1-piperazinyl]-2-butanol monohydrochloride monohydrate

This compound was prepared according to the procedure of Example 97. A mixture of 3.0 g (0.015 mole) of 1-(4-methoxyphenyl)piperazine, 3.4 g (0.015 mole) of 4-chloro-1-(4-fluorophenoxy)-2-butanol, 5.2 g (0.05 mole) of anhydrous sodium carbonate and 0.1 g of potassium iodide in a total volume of 200 ml of 1-butanol gave an oil as residue. The hydrochloride was formed in 2-propanol saturated with hydrogen chloride and the collected solid was recrystallized from methanol-water-ethyl ether to give 3.2 g (48%) of white solid, m.p. 195°-202° C.

Analysis: Calculated for C₂₁ H₂₈ ClFN₂ O₃.H₂ O: C, 58.81; H, 7.05; N, 6.53. Found: C, 58.98; H, 6.81; N, 6.48.

EXAMPLE 119 1-(4-Fluorophenoxy)-4-[4-(4-methoxyphenyl)-1-piperazinyl]-2-butanol

This compound was prepared according to the procedure of Example 110. A mixture of 5.8 g (0.0267 mole) of 4-chloro-1-(4-fluorophenoxy)-2-butanol, 5.1 g (0.0267 mole) of 1-(4-methoxyphenyl)-piperazine, 9.4 g (0.089 mole) of anhydrous sodium carbonate, and 0.16 g of potassium iodide in a total volume of 200 ml of 1-butanol gave a brown oil. Upon trituration with petroleum ether (30°-60° C.), the oil solidified. The collected solid was recrystallized from isopropyl ether to yield 6.4 g (64%) of white, crystalline solid, m.p. 78°-80° C.

Analysis: Calculated for C₂₁ H₂₇ FN₂ O₃ : C, 67.36; H, 7.27; N, 7.48. Found: C, 67.35; H, 7.36; N, 7.53.

EXAMPLE 120 1-(3,5-Dimethylphenoxy)-4-[4-(4-fluorophenyl)-1-piperazinyl]-2-butanol monohydrochloride monohydrate

This compound was prepared according to the procedure of Example 97. A mixture of 2.5 g (0.01 mole) of 4-chloro-1-(3,5-dimethylphenoxy)-2-butanol, 1.8 g (0.01 mole) of 1-(4-fluorophenyl)piperazine, 5.2 g (0.05 mole) of anhydrous sodium carbonate and 0.1 g of potassium iodide in a total volume of 200 ml of 1-butanol gave a golden oil as residue. The hydrochloride was formed in 2-propanol saturated with hydrogen chloride and the collected solid was recrystallized from methanol-water-ethyl ether to give 1.6 g (37%) of white crystalline solid, m.p. 176°-180° C.

Analysis: Calculated for C₂₂ H₃₀ ClFN₂ O₂.H₂ O: C, 61.89; H, 7.56; N, 6.56. Found: C, 61.84; H, 7.28; N, 6.54.

EXAMPLE 121 1-(4-Fluorophenoxy)-4-[4-(4-acetylphenyl)-1-piperazinyl]-2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 2.0 g (0.01 mole) of 4-(1-piperazino)acetophenone, 2.2 g (0.01 mole) of 4-chloro-1-(4-fluorophenoxy)-2-butanol, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave 2.7 g (69%) of pale yellow solid, m.p. 114°-116° C. The recrystallizing solvent used was isopropyl alcohol.

Analysis: Calculated for C₂₂ H₂₇ FN₂ O₃ : C, 68.37; H, 7.04; N, 7.25. Found: C, 68.37; H, 7.15; N, 7.28.

EXAMPLE 122 1-(4-Chlorophenoxy)-4-[4-(4-acetylphenyl)-1-piperazinyl] 2-butanol

This compound was prepared according to the procedure of Example 78. A mixture of 2.0 g (0.01 mole) of 4-(1-piperazino)acetophenone, 2.4 g (0.01 mole) of 4-chloro-1-(4-chlorophenoxy)-2-butanol, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave 2.8 g (70%) of pale yellow solid, m.p. 123°-125° C. The recrystallizing solvent was isopropyl alcohol.

Analysis: Calculated for C₂₂ H₂₇ ClN₂ O₃ : C, 65.58; H, 6.75; N, 6.95. Found: C, 65.60; H, 6.82; N, 6.95.

The invention further provides pharmaceutical compositions for administration to a living animal comprising, as active ingredients, at least one of the compounds according to the invention in association with a pharmaceutical carrier or excipient. The compounds are thus presented in a form suitable for oral, rectal, parenteral or intracardial administration. Thus, for example, compositions for oral administration are preferably solids and can take the form of capsules, tablets or coated tablets containing carriers conveniently used in the pharmaceutical art. Suitable tableting excipients include lactose, potato and maize starches, talc, gelatin and stearic and silicic acids, magnesium stearate and polyvinyl pyrrolidone.

For parenteral administration, the carrier or excipient can be a sterile, parenterally acceptable liquid, e.g., water, or a parenterally acceptable oil, e.g., arachis oil, contained in ampoules.

In compositions for rectal administration the carrier can comprise a suppository base, e.g., cocoa butter, or a glyceride.

Advantageously, the compositions are formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredients. Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred dosage unit forms according to the invention. Each dosage unit adapted for oral administration may conveniently contain 10 to 40 mg. of the active ingredient; each dosage unit adapted for intracardial or intravenous administration may conveniently contain 1 to 2 mg. per cc. of the active ingredient; whereas each dosage unit adapted for intramuscular administration may conveniently contain 5 to 10 mg. per cc. of the active ingredient.

Examples of compositions within the preferred ranges given are as follows:

    ______________________________________                                         Capsules                                                                       Ingredients       Per Cap.                                                     ______________________________________                                         1.      Active ingredient                                                                            10.00       mg.                                          2.      Lactose       146.000     mg.                                          3.      Magnesium Stearate                                                                           4.000       mg.                                          ______________________________________                                    

Procedure

1. Blend 1, 2 and 3.

2. Mill this blend and blend again.

3. This milled blend is then filled into #1 hard gelatin capsules.

    ______________________________________                                         Tablets                                                                        Ingredients       Mg./Tab.                                                     ______________________________________                                         1.      Active ingredient                                                                            10.0        mg.                                          2.      Corn Starch   20.0        mg.                                          3.      Alginic acid  20.0        mg.                                          4.      Sodium alginate                                                                              20.0        mg.                                          5.      Magnesium Stearate                                                                           1.3         mg.                                          ______________________________________                                    

Procedure

1. Blend 1, 2, 3 and 4.

2. Add sufficient water portionwise to blend from step #1 with careful stirring after each addition. Such additions of water and stirring continue until the mass is of a consistency to permit its conversion to wet granules.

3. The wet mass is converted to granules by passing it through the oscillating granulator, using 8-mesh screen.

4. The wet granules are then dried in an oven at 140° F.

5. The dried granules are then passed through an oscillating granulator, using a 10-mesh screen.

6. Lubricate the dry granules with 0.5% magnesium stearate.

7. The lubricated granules are compressed on a suitable tablet press.

    ______________________________________                                         Intravenous Injection                                                          Ingredients          Per ml.                                                   ______________________________________                                         1.      Active ingredient                                                                               1.0      mg.                                          2.      pH 4.0 Buffer solution q.s. to                                                                  1.0      ml.                                          ______________________________________                                    

Procedure

1. Dissolve the active ingredient in the buffer solution.

2. Aseptically filter the solution form step #1.

3. The sterile solution is now aseptically filled into sterile ampuls.

4. The ampuls are sealed under aseptic conditions.

    ______________________________________                                         Intramuscular Injection                                                        Ingredients         Per ml.                                                    ______________________________________                                         1.      Active ingredient                                                                              5.0       mg.                                          2.      Isotonic Buffer solution                                                                       1.0       ml.                                                  4.0 q.s. to                                                            ______________________________________                                    

Procedure

1. Dissolve the active ingredient in the buffer solution.

2. Aseptically filter the solution from step #1.

3. The sterile solution is now aseptically filled into sterile ampuls.

4. The ampuls are sealed under aseptic conditions.

    ______________________________________                                         Suppositories                                                                  Ingredients         Per Supp.                                                  ______________________________________                                         1.     Active ingredient                                                                               10.0       mg.                                         2.     Polyethylene Glycol 1000                                                                        1350.0     mg.                                         3.     Polyethylene Glycol 4000                                                                        450.0      mg.                                         ______________________________________                                    

Procedure

1. Melt 2 and 3 together and stir until uniform.

2. Dissolve #1 in the molten mass from step 1 and stir until uniform.

3. Pour the molten mass from step 2 into suppository molds and chill.

4. Remove the suppositories from molds and wrap.

Pharmaceutical compositions having cardiac arrhythmia inhibiting activity and minimal β-adrenergic blocking activity, in dosage unit form, comprising a pharmaceutical carrier and a cardiac arrhythmia inhibiting amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof are therefore one of the objects of this invention.

Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, method, and compositions of the present invention without departing from the spirit or scope thereof, and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims. 

What is claimed is:
 1. A compound selected from 4-cyclohexylamino-1-(orthomethoxyphenoxy)-2-butanol or a pharmaceutically acceptable acid addition salt thereof.
 2. The compound of claim 1 which is 4-cyclohexylamino-1-(orthomethoxyphenoxy)-2-butanol.
 3. A pharmaceutical composition having cardiac arrhythmia inhibiting activity and minimal beta-adrenergic blocking activity comprising (a) a cardiac arrhythmia inhibiting amount of a compound selected from the group consisting of 4-cyclohexylamino-1-(ortho-methoxyphenoxy)-2-butanol or a pharmaceutically acceptable acid addition salt thereof, and (b) a pharmaceutical carrier thereof.
 4. The pharmaceutical composition of claim 3 in which the compound is 4-cyclohexylamino-1-(ortho-methoxyphenoxy)-2-butanol.
 5. A method of inhibiting cardiac arrhythmia with minimal beta-adrenergic blocking activity which comprises administering internally to an animal in need of said treatment an effective cardiac arrhythmia inhibiting amount of a compound selected from the group consisting of 4-cyclohexylamino-1-(ortho-methoxyphenoxy)-2-butanol or a pharmaceutially acceptable acid addition salt thereof.
 6. A method of claim 5 in which the compound is 4-cyclohexylamino-1-(ortho-methoxyphenoxy)-2-butanol. 